Antiplatelet drugs for the treatment and prevention of vascular disease: A review of recent clinical trials

Transcription

1 Antiplatelet drugs for the treatment and prevention of vascular disease: A review of recent clinical trials Niteesh K. Choudhry, MD, PhD Nihar Desai, MD, MPH Michael Fischer, MD, MS Jerry Avorn, MD Eimir Hurley, MBiostat

2 Introduction Antiplatelet drugs are used for the prevention of myocardial infarction (MI), stroke, and other cardiovascular events. Choosing the right antiplatelet therapy requires an understanding of the benefits and risks of the specific regimens in different clinical settings. Drug Brand Name Type Aspirin generic Irreversible COX-1 inhibitor Clopidogrel Plavix, generic Irreversible ADP receptor blocker Prasugrel Effient Irreversible ADP receptor blocker Ticagrelor Brilinta Reversible ADP receptor blocker Dipyridamole Persantine, generic Thrombus inhibitor Aspirin/ dipyridamole Aggrenox Combination therapy

3 Summary of recommendations Condition Recommended Treatment Evidence Primary prevention aspirin only for patients in whom benefits outweigh risks POPADAD, JPAD, USPSTF Stable angina aspirin Antiplatelet Trialists Collaboration, CHARISMA Acute coronary syndromes [unstable angina, non- ST-segment elevation MI (NSTEMI), and ST-segment elevation MI (STEMI)] clopidogrel + aspirin for 1 year. prasugrel + aspirin or ticagrelor + aspirin may be a superior alternative for some ACS patients CURE, COMMIT, CLARITY, CHARISMA, CAPRIE, TRITON, PLATO Past MI Elective PCI clopidogrel for high-risk patients,* aspirin for all others clopidogrel + aspirin for at least a year CHARISMA, CAPRIE CREDO Stroke clopidogrel or aspirin + dipyridamole MATCH, CHARISMA, ESPS2, ESPRIT, PRoFESS, SPS3 Peripheral artery disease clopidogrel CHARISMA, CAPRIE * High-risk patients: history of coronary artery disease, stroke, or TIA; events involving multiple vascular beds; or 2 ischemic events.

4 Outline Epidemiology Acute coronary syndrome (ACS) Stable coronary artery disease (CAD) Stroke Peripheral arterial disease (PAD) Primary prevention Miscellaneous topics

5 Epidemiology

6 The majority of adult Americans have cardiovascular disease (CVD)* MORE THAN 80% OF PATIENTS 80 YEARS AND OLDER HAVE CVD 100% 90% 83% 87% Percent of Population with CVD 80% 70% 60% 50% 40% 30% 20% 10% 13% 10% 40% 34% 70% 71% Men Women 0% Age groups Ø SOURCE: American Heart Association Statistics. Circulation, 2013;127:e6-e245 * Cardiovascular disease (CVD)- includes data on coronary heart disease, heart failure, stroke, and hypertension.

7 More than 1 million patients have a myocardial infarction in the U.S. every year. 250 New and Recurrent MI or fatal CHD (000s) Men Women Age groups Ø SOURCE: American Heart Association Statistics. Circulation, 2013;127:e6-e245 Includes myocardial infarction (MI) and fatal CHD but not silent MI.

8 Stroke also is also very common 13% OF AMERICANS 80 YEARS AND OLDER HAVE HAD A STROKE % 14.00% 14.0% 14.0% 12.00% Percent of Population 10.00% 8.00% 6.00% 6.0% 7.0% Men Women 4.00% 2.00% 2.0% 2.0% 0.4% 0.6% 0.00% Age groups Ø SOURCE: American Heart Association Statistics. Circulation, 2013.

9 CVD is the leading cause of death in the U.S. CVD ACCOUNTS for 45% OF DEATHS PER YEAR Deaths (000s) Men Women CVD Cancer Accidents Respiratory Type 2 diabetes Alzheimers Ø SOURCE: American Heart Association Statistics. Circulation, :e6-e245 Deaths shown for 2009.

10 Cardiovascular disease costs more than $300 billion annually in the US 250 $312 billion 200 $195.2 Billions of Dollars $51.0 $38.6 $ Heart disease Hypertension Stroke Other CVD Ø SOURCE: American Heart Association Statistics. Circulation, 2013; 127:e6-e245 Direct and indirect costs of cardiovascular disease and stroke.

11 Acute coronary syndrome (ACS)

12 Acute coronary syndromes (ACS) ACS includes a spectrum of clinical conditions including: Unstable angina (UA) Non- ST- segment elevation myocardial infarction (NSTEMI) ST-segment elevation MI (STEMI)

13 Acute Coronary Syndromes Ø Source ACC/AHA Guidelines, Circulation. 2004;110:e82-e292

14 Aspirin greatly reduces the risk of vascular events in acute myocardial infarction The benefit of of aspirin for patients with ST-segment elevation myocardial infarction (STEMI) is based on 15 trials of approximately 19,000 patients The benefit of aspirin in non- STsegment elevation myocardial infarction (NSTEMI) or unstable angina (UA) is based on 12 trials of > 5,000 patients Percentage Vascular Events 16% 14% 12% 10% 8% 6% 4% 2% 10% 14% Percentage Vascular Events 14% 12% 10% 8% 6% 4% 2% 8% 13% 0% Aspirin Placebo 0% Aspirin Placebo Ø SOURCE: Antiplatelet Trialists Collaboration; BMJ 2002; 324: 71

15 Use low dose aspirin: Higher doses of aspirin are not superior to lower doses in decreasing vascular events and are associated with a greater risk of bleeding LOW DOSE ASPIRIN WAS AT LEAST AS EFFECTIVE AS HIGH DOSE ASPIRIN RATES OF BLEEDING WAS MUCH LOWER WITH LOW DOSE ASPIRIN Percent of patients who had a vascular event 14% 12% 10% 8% 6% 4% 2% 0% 9.6% Low dose 11.7% High dose Percent of patients who had a bleeding event 5% 4% 4% 3% 3% 2% 2% 1% 1% 0% 2.4% Low dose 4.2% High dose Ø SOURCES: NEJM 2001; 345(7) :

16 Clopidogrel plus aspirin is more effective than aspirin alone in reducing vascular events and death in patients with ACS CURE, NEJM 2001; 345 (7): Patients within 24 hours of ACS (NSTEMI/UA only (N=12,562) Clopidogrel 75mg + aspirin 75mg - 375mg Up to 12 months Aspirin 75mg 375mg Non-fatal MI, stroke, CV death 9.3% xx% 11.4% xx% Relative risk reduction= 20% P<0.001 Major bleeding* Relative risk increase = xx% P=xx *Major bleeding refers to non-cabg related TIMI major bleeding and is defined as intracranial bleeding, clinically overt signs of hemorrhage associated with a drop in hemoglobin of >=5g/dl, and/or bleeding that directly results in death within 7 days but which is unrelated to coronary artery bypass surgery

17 Patients randomized to receive clopidogrel plus aspirin post ACS had a relative reduction of 20% in the rate of CV death, stroke or MI Dual antiplatelet clopidogrel plus aspirin is recommended for up to 1 year for patients with ACS The benefits of continuing dual therapy beyond one year are the subject of ongoing research CURE, NEJM 2001; 345 (7):

18 Prasugrel plus aspirin in patients with ACS undergoing PCI is more effective than clopidogrel plus aspirin but causes more bleeds TRITON-TIMI 38, NEJM 2007; 357(20): ACS patients undergoing PCI (N=13,608) 74% UA/NSTEMI 26% STEMI Prasugrel 10mg + aspirin 75mg - 162mg Up to 15 months Clopidogrel 75mg plus aspirin 75mg 162mg Non-fatal MI, stroke, CV death 9.9% 2.4% 12.1% 1.8% HR= 0.81* P<0.001 Major bleeding** HR= 1.32* P=0.03 *Odds of primary outcome reduced by 19% in the prasugrel group, while the odds of bleeding were increased by 32% **Major bleeding refers to non-cabg related TIMI major bleeding and is defined as intracranial bleeding, clinically overt signs of hemorrhage associated with a drop in hemoglobin of >=5g/dl, and/or bleeding that directly results in death within 7 days but which is unrelated to coronary artery bypass surgery

19 Patients undergoing PCI post ACS randomized to prasugrel had less events but more bleeds 15 Primary Efficacy End Point Clopidogrel Events End Point (%) 10 Prasugrel 9.9 Hazard ratio, 0.81; 95% CI, ; P< Key Safety End Point Prasugrel Clopidogrel Days after Randomization Events Hazard ratio, 1.32; 95% CI, ; P=0.03 In patients with ACS or elective PCI, there is good evidence for use of dual antiplatelet therapy for at least 1 year. The appropriate duration of dual therapy for patients undergoing PCI after MI may be as long as 15 months. TRITON-TIMI 38, NEJM 2007; 357(20):

20 Prasugrel plus aspirin and clopidogrel plus aspirin have similar efficacy and bleeding rates in ACS patients not undergoing PCI TRILOGY - ACS, NEJM 2012; 367(14): ACS patients <75 years (not undergoing PCI) (N=7,234) 74% UA/NSTEMI 26% STEMI Prasugrel 10mg + aspirin Up to 30 months Clopidogrel 75mg plus aspirin Non-fatal MI, stroke, CV death* 13.9% 2.1% 16.0% 1.5% HR= 0.91 p=0.21 ns Major or minor bleeding* HR= 1.3 p=0.27 ns *Results presented here are for the primary outcomes which were restricted to patients less than 75 years of age

21 Prasugrel was not superior to clopidogrel in patients with ACS patients without PCI in reducing the rate of CV death, MI or stroke Primary End Point Primary End Point (%) Primary Efficacy End Point TIMI Major Bleeding Clopidogrel Prasugrel Days Clopidogrel plus aspirin is the best-tested regimen in this setting and has become the standard of care. TRILOGY - ACS, NEJM 2012; 367(14):

22 Ticagrelor plus aspirin in patients with ACS is more effective than clopidogrel plus aspirin but causes more bleeds PLATO, NEJM 2010; 361(11): ACS patients (N=18,624) 60% UA/ NSTEMI 38% STEMI Ticagrelor 90mg bd + aspirin 75mg - 325mg Up to 12 months Clopidogrel 75mg plus aspirin 75mg - 325mg Non-fatal MI, stroke, CV death 9.8% 2.8% 11.7% 2.2% HR= 0.84* P<0.001 Major bleeding** HR= 1.25* P=0.03 *Odds of primary outcome reduced by 16% in the ticragrelor group, while the odds of bleeding were increased by 25% **Major bleeding refers to non-cabg related TIMI major bleeding and is defined as intracranial bleeding, clinically overt signs of hemorrhage associated with a drop in hemoglobin of >=5g/dl, and/or bleeding that directly results in death within 7 days but which is unrelated to coronary artery bypass surgery

23 Summary: Intensive antiplatelet therapy in ACS reduces ischemic events more than aspirin alone Ø SOURCES: Lancet 2009; 373: , NEJM 2001; 345 (7): , NEJM 2007;357 (20); , NEJM 2010; 361(11):

24 However intensive antiplatelet therapy increases the risk of major bleeding Ø SOURCES: Lancet 2009; 373: , NEJM 2001; 345 (7): , NEJM 2007;357 (20); , NEJM 2010; 361(11): Major bleeding is defined as intracranial bleeding, clinically overt signs of hemorrhage associated with a drop in hemoglobin of >=5g/dl, and/or bleeding that directly results in death within 7 days but which is unrelated to coronary artery bypass surgery.

25 ACS: Bottom Line 1 Dual therapy with clopidogrel + aspirin for at least 1 year is the currently recommended treatment for all ACS patients. Aspirin should be continued indefinitely. 2 More intensive antiplatelet therapy with prasugrel + aspirin or ticagrelor + aspirin may benefit some patients but it is associated with an increased risk of bleeding.

26 Stable coronary artery disease (CAD)

27 Aspirin substantially reduces the risk of vascular events in patients with stable angina or prior MI The benefit of aspirin for patients with stable angina is based on 7 trials of approx. 3,000 patients The benefit of aspirin for patients with a prior MI is based on 12 trials of approx. 19,000 patients 10% 9.4% 9% 8% 7% 6% 5% 4% 3% 2% 1% 0% 8.2% Aspirin Placebo Percent of patients who had a vascular event 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% 13.5% Aspirin 17.0% Placebo Ø SOURCE: Antiplatelet Trialists Collaboration; BMJ 2002; 324: 71

28 The CAPRIE trial showed that clopidogrel alone was no more effective than aspirin in the prevention of vascular events in a sub-group of patients with recent MI CAPRIE, Lancet 1996; 348: 1329 Recent - but not acute MI (N=11,630) Clopidogrel 75mg Up to 3 years Aspirin 325mg Risk of composite of ischemic stroke, MI, or vascular death 5.0% 1.4% 4.8% 1.6% Relative risk increase= 3.7% p=0.66 Bleeding* ns The CAPRIE trial randomized over 19,000 patients with atherosclerotic vascular disease manifested as either recent ischemic stroke, recent myocardial infarction or symptomatic peripheral arterial disease. Results presented here are for the subgroup of patients with recent MI * Classified as any severe bleeding disorder of the total population (N=19,185)

29 There was no significant difference between clopidogrel and aspirin for the subgroup of patients with a recent MI CAPRIE, Lancet 1996; 348: 1329 ASPIRIN BETTER CLOPIDOGREL BETTER Stroke MI PAD All patients Relative-risk reduction (%) Overall, clopidogrel was more effective than aspirin in the total population but the absolute benefit was very small and was largely attributable to patients with peripheral arterial disease (PAD)

30 Adding clopidogrel to aspirin in those with a history of MI does not significantly reduce the risk of stroke, MI or death CARISMA, NEJM 2006; 354 (16): Established CV disease or multiple risk factors (N=15,603) Clopidogrel 75mg + aspirin 75mg - 162mg Up to 30 months Aspirin 75mg 162mg Non-fatal MI, stroke, CV death Severe bleeding 6.8% 1.7% 7.3% 1.3% Relative risk reduction= 7% p=0.22 Relative risk increase = 31% p=0.09

31 Clopidogrel plus aspirin was no more effective than aspirin alone in preventing vascular events in those with a prior MI A subgroup of patients with symptomatic vascular disease showed a slight benefit from combination therapy this result was only of borderline significance. CARISMA, NEJM 2006; 354 (16):

32 Adding a proton pump inhibitor (PPI) to aspirin for patients with a GI bleed while on aspirin, is more effective in preventing recurrent bleeds than switching to clopidogrel NEJM 2005; 352: Patients who experienced a GI bleed while taking aspirin to prevent vascular disease Ulcer healed using a PPI Clopidogrel 75mg Up to 12 months Risk of recurrent ulcer bleeding 8.6% (N=320) Aspirin 80mg daily plus esomeprazole 20mg twice daily 0.7% Absolute difference =7.9%, p=0.001 For patients who have a GI bleed while on aspirin, adding a proton-pump inhibitor is more effective in preventing another bleed than using clopidogrel instead of aspirin

33 Adding a proton pump inhibitor (PPI) to aspirin for patients with a GI bleed while on aspirin, is more effective in preventing recurrent bleeds than switching to clopidogrel NEJM 2005; 352:

34 Stable CAD: Bottom Line 1 Most patients with stable CAD or a history of MI (but not an acute MI) should be treated with aspirin alone (81mg/day) 2 Clopidogrel alone should be used in the case of aspirin allergy or in highrisk patients (those with a history of bypass surgery, multiple MIs, a prior stroke, arterial disease in two or more areas, diabetes, or high cholesterol) 3 For patients who have a GI bleed while on aspirin, adding a proton-pump inhibitor is more effective in preventing another bleed than using clopidogrel instead of aspirin

35 Stroke

36 Aspirin greatly reduces the risk of vascular events in patients with stroke or TIA The benefit of aspirin for patients with acute stroke is based on 7 trials of approx. 41,000 patients The benefit of aspirin for patients with prior stroke/tia is based on 21 trials of approx. 23,000 patients Percent of patients who had a vascular event 10.0% 9.0% 8.0% 7.0% 6.0% 5.0% 4.0% 3.0% 2.0% 1.0% 0.0% 8.2% Aspirin 9.1% Placebo Percent of patients who had a vascular event 25% 20% 15% 10% 5% 0% 17.8% Aspirin 21.4% Placebo Ø SOURCE: Antiplatelet Trialists Collaboration; BMJ 2002; 324: 71

37 The CAPRIE trial showed that clopidogrel alone was no more effective than aspirin in the prevention of vascular events in a sub-group of patients with stroke CAPRIE, Lancet 1996; 348: 1329 Clopidogrel 75mg Risk of composite of ischemic stroke, MI, or vascular death Bleeding* Recent stroke (>1 week; <6 months) (N=6431) Up to 3 years Aspirin 325mg 7.2% 1.4% 7.7% 1.6% Relative risk reduction= 7.3%, p=0.26 ns Based on these results clopidogrel or aspirin are an equal choice in patients with recent stroke. In several high-risk subgroups (i.e., those with a history of bypass surgery, events involving multiple vascular beds, a history of more than one ischemic event, diabetes, or high cholesterol) clopidogrel did appear superior to aspirin * Classified as any severe bleeding disorder in the total study population (N=19,185)

38 There was no significant difference between clopidogrel and aspirin for the subgroup of patients with a recent stroke CAPRIE, Lancet 1996; 348: 1329 ASPIRIN BETTER CLOPIDOGREL BETTER Stroke MI PAD All patients Relative-risk reduction (%)

39 Clopidogrel plus aspirin in stroke patients does not prevent more vascular events than aspirin alone, but significantly increases the risk of major bleeding MATCH, 2004 Lancet 2004; 364: 331. Stroke or TIA within previous 3 months (and 1 of prior stroke, prior MI, angina, DM, symptomatic PVD) Clopidogrel 75mg + aspirin 75mg Up to 18 months Risk of composite of ischemic stroke, MI, vascular death, re-hosp for acute ischemic event) 16.7% 1.9% 17.7% 0.6% Risk of major bleeding (N=7,559) Aspirin 75mg Relative risk reduction = 6% P=0.244 Relative risk increase= 68% P< Avoid dual therapy clopidogrel plus aspirin in acute stroke as the risk of bleeding outweighs the benefit.

40 Combining clopidogrel with aspirin for patients also does not provide benefit for patients with lacunar strokes SPS3, NEJM 2012; 367: Recent symptomatic lacunar infarct (N=3,020) Clopidogrel 75mg + aspirin 325mg Up to 8 years Aspirin 325mg Recurrent strokes, including ischemic stroke or intracranial hemorrhage 2.5%/yr 2.7%/yr HR=0.92 P=0.48 Risk of major bleeding 2.1%/yr 1.1%/yr HR=1.97% p<0.001 Avoid dual therapy clopidogrel plus aspirin in patients with lacunar stroke as the risk of bleeding is doubled in those assigned dual therapy However, patient with additional indications, such as PCI may require dual therapy.

41 Dipyridamole plus aspirin reduces the risk of a composite outcome of recurrent strokes, including ischemic stroke or intracranial hemorrhage, more than aspirin alone. ESPRIT, Lancet 2006; 367: TIA or minor ischemic stroke within previous 6 months (N=2,739) Dipyridamole 200 mg + aspirin mg twice daily Up to 5 years Aspirin mg, (median dose 75 mg) Vascular events (including intracranial hemorrhage) 13% 2.6% 16% 3.9% HR = 0.80 (95% CI: 0.69 to 0.98) Risk of major bleeding HR= 0.67 (95% CI: 0.44 to 1.03) ns When bleeding complications were removed from the primary outcome (to compare across other trials) the difference between the two groups was non significant. Interestingly, the rate of bleeding was actually lower in patients with dual therapy than monotherapy. However this was not a significant finding.

42 Clopidogrel alone and aspirin plus dipyridamole are equally effective at reducing recurrent stroke PROFESS, NEJM 2008; 359:1238 Ischemic stroke (symptoms > 24 hr or < 24 hr with radiologic confirmation) within 90 days Dipyridamole 200 mg + aspirin 25 twice daily Up to 3.5 years Recurrent stroke 9.0% 4.1% 8.8 % 3.6% Risk of major bleeding (N=20,332) Clopidogrel 75 mg once daily HR= 1.01 (95% CI: 0.92 to 1.11) ns HR = 1.15 (95% CI: 1.00 to 1.32) The two treatments are equivalent in the prevention of recurrent stroke in those with previous ischemic stroke Aspirin plus dipyridamole may cause a slightly higher risk of bleeding than clopidogrel alone

43 A summary of dual antiplatelet therapy in stroke In patients with ischemic stroke or TIA in the prior 3 months, the evidence favors clopidogrel alone or dipyridamole plus aspirin - Avoid dual therapy clopidogrel plus aspirin unless a patient has additional indications, such as PCI Use aspirin for most patients with a remote history of stroke

44 Stroke: Bottom Line 1 Clopidogrel or aspirin-dipyridamole are effective for the prevention of recurrent vascular events in patients with recent stroke. 2 Clopidogrel should be particularly considered in high-risk stroke patients (bypass surgery, events involving multiple vascular beds, two or more ischemic events, diabetes, or high cholesterol), and in patients with aspirin allergy. 3 Aspirin monotherapy is recommended for patients with a more remote history of stroke. 4 Dual antiplatelet therapy with aspirin and clopidogrel should be avoided unless there is a compelling clinical indication, such as ACS and/or PCI

45 Peripheral arterial disease (PAD)

46 Aspirin reduces the risk of vascular events in patients with PAD Efficacy of antiplatelet therapy (mainly aspirin) for PVD based on 42 trials of approximately 9200 patients with PAD Percent of patients who had a vascular event 8.0% 7.0% 6.0% 5.0% 4.0% 3.0% 2.0% 1.0% 5.8% 7.1% 0.0% Aspirin Placebo Ø SOURCE: Antiplatelet Trialists Collaboration; BMJ 2002; 324: 71

47 The CAPRIE trial showed that clopidogrel alone was significantly more effective than aspirin in the prevention of vascular events in patients with PAD CAPRIE, Lancet 1996; 348: 1329 Intermittent claudication Clopidogrel 75mg Risk of composite of ischemic stroke, MI, or vascular death Bleeding* Or History of surgically repaired claudication (N= 6452) Up to 3 years Aspirin 325mg 3.7% 4.9% Relative risk reduction= 24%, (95% CI: 8.9% to 36.2%) 1.4% 1.6% ns Patients with peripheral artery disease derive greater benefit from clopidogrel than aspirin in the reduction of vascular events. * Classified as any severe bleeding disorder in the total study population (N=19,185)

48 PAD: Bottom Line 1 Aspirin is more effective than placebo in reducing vascular events in patients with peripheral artery disease. 2 Clopidogrel monotherapy is recommended for patients with PAD. Its advantage over aspirin is greater in PAD than in other CVD patient populations

49 Primary prevention

50 The absolute benefits of aspirin in primary prevention are small especially considering risk of therapy ASPIRIN BETTER PLACEBO BETTER Outcome Odds ratio (95% CI) Non-fatal MI 0.80 ( ) Total CVD events 0.90 ( ) CVD mortality 0.99 ( ) Non-CVD mortality 0.92 ( ) Total bleeds 1.70 ( ) Odds ratio (95% CI) Meta-analysis of nine clinical trials (n = 102,621) that evaluated the role of aspirin for the primary prevention of vascular disease. Ø SOURCE: Arch Intern Med 2012; 172: 209..

51 The role of aspirin for primary prevention in diabetes has become less certain Two recent trials failed to find a significant reduction in vascular events in patients with diabetes with no known coronary artery disease What were the main results? Trial name Patient population Doses Aspirin Rate of vascular events Placeb o Absolute difference Aspirin Risk of major bleeding Placebo Absolute difference POPADAD (N=1,276) DM and ABI 0.99 but no CAD aspirin 100 mg daily vs placebo 18.2% 18.3% ns 4.4% 4.9% ns JPAD (N=2,539) DM but no CAD aspirin 81 or 100 mg daily vs placebo 5.4% 6.7% ns 0.003% 0 ns DM= Diabetes Mellitus, ABI= Ankle brachial index Ø SOURCE: BMJ 2008; 337: a1840; JAMA 2008; 300: 2134

52 Weigh up the risks and benefits of aspirin based on patient characteristics Because of bleeding risk, aspirin should be used for primary prevention only if risk for cardiovascular disease exceeds these thresholds. Ø SOURCE: USPSTF guidelines. Ann Intern Med 2009; 150: 396.

53 Aspirin for primary prevention: Bottom Line 1 Some patients who receive aspirin for primary prevention (e.g., patients with low-risk diabetes) may derive less benefit than has been traditionally believed. 2 Aspirin should be prescribed for primary prevention only in patients for whom the benefits of therapy outweigh its harms.

54 Miscellaneous topics

55 Costs vary widely for different regimens this is particularly important for drugs that have very similar risk-benefit profiles Average monthly price for commonly used antiplatelet agents

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